Scientists at the University of Toronto examined fungi in the mucus of patients with cystic fibrosis and discovered how one particular fungal species has evolved to defend itself against neighboring bacteria.

Especially ubiquitous in the lungs of cystic fibrosis patients Candida albicans is an opportunistic pathogen that usually causes no harm but can turn dangerous if an immune system becomes compromised. In fact, this fungus is among the most common causes of bloodstream infections, such as sepsis. As the population living with weakened immune systems has risen substantially over the past two decades, e.g., people living with HIV, having organ transplants, or undergoing cancer chemotherapy are some examples, opportunistic fungal pathogens like this one have become an even greater threat.

“Fungi have a staggering impact on human health, infecting billions of people around the world and killing 1.5 million every year,” says Leah Cowen, Ph.D., University of Toronto Molecular Genetics professor and Canada Research Chair in Microbial Genomics and Infectious Disease, and lead researcher on the study (“Global Analysis of the Fungal Microbiome in Cystic Fibrosis Patients Reveals Loss of Function of the Transcriptional Repressor Nrg1 as a Mechanism of Pathogen Adaptation”) published in PLOS Pathogens. “And yet, they are underappreciated and not well understood.”

C. albicans can morph from a round, single-celled yeast into a long stringy structure, allowing it to adapt to different environments and making it exceptionally harmful. For this study, researchers analyzed 89 mucus samples from 28 cystic fibrosis patients, using both high-throughput genetic sequencing as well as culture-based analysis. C. albicans was predictably prevalent.

What surprised the researchers, however, was that some of this fungi began shifting into its stringy shape without any environmental cue. Usually this filamentation doesn't happen spontaneously, but is triggered by the presence of certain substances, such as blood. To see if there could be a genetic explanation, the researchers sequenced the genomes of these samples and found a common denominator. All but one had genetic mutations in a gene known to repress the change shape, NRG1.

“This was a smoking gun,” notes Dr. Cowen. “This gene makes a protein that stops filamentation like a brake. Because of these genetic mutations, the fungi lost this brake and were not able to stop these long strings from forming.”

To find out why certain strains of this fungus would have developed this genetic variation, researchers looked to neighboring bacteria. As part of an ongoing battle between microbes, certain bacteria, which are also found in cystic fibrosis patients, secrete molecules preventing the fungus from changing into its stringy shape. The researchers tried exposing the mutated fungus to these bacterial rivals. Instead of responding to the bacterial signals, the fungus kept to its stringy form. The researchers believe these fungi have evolved to counter the tactics of their bacterial rivals.

“We think the interaction between bacteria and fungus drove this,” continues Dr. Cowen. “Usually losing control isn't a very good thing, but in this case it may be a great defense mechanism for Candida. These fungi have essentially learned to ignore the bacteria.”

Dr. Cowen is continuing research into the impact of fungal pathogens in cystic fibrosis patients, who are unable to clear microbes from their airways and suffer reduced lung function as a result. The goal is to eventually develop treatments for this fatal genetic disease. She is also seeking to better understand the role of fungi in variety of other conditions.

 








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